This project, in part, represents an extension of work previously reported as Project Numbers Z01 DK69037, Z01 DK069097 and Z01 DK069000. It also reports on continuation of work previously reported under Project Numbers DK069036-23, DK069063-17, and DK069100-06. All work related to diabetic kidney disease, except for the genetics of diabetic kidney disease, is now reported under this single project. In the past year, we described a pathway definitively linking ATP-binding cassette A1 (ABCA1) deficiency to cardiolipin-driven mitochondrial dysfunction. We demonstrated that this pathway is relevant to diabetic kidney disease and that ABCA1 inducers or inhibitors of cardiolipin peroxidation may each represent therapeutic strategies for the treatment of established diabetic kidney disease. We also reported results of a study in which a group of 48 Pima Indians with type 2 diabetes underwent 2 research kidney biopsies a mean of 9.3 years apart. We demonstrated worsening of kidney structural lesions, including increased glomerular basement membrane width and mesangial fractional volume, and a reduction in the surface density of peripheral glomerular basement membrane. These structural changes were associated with increasing urine albumin excretion, but were not associated with declining glomerular filtration rate (GFR), suggesting that in American Indians with type 2 diabetes and preserved glomerular filtration rate at baseline, increasing albuminuria reflects progression of earlier structural lesions, whereas early GFR decline may not accurately reflect such lesions. We examined 194 circulating inflammatory proteins using an aptamer-based SOMAscan platform in subjects from three independent cohorts with type 1 and type 2 diabetes. In each cohort, we identified an extremely robust kidney risk inflammatory signature (KRIS), consisting of 17 proteins enriched in tumor necrosis factor-receptor superfamily members, that was associated with a 10-year risk of end-stage renal disease. All these proteins had a systemic, non-kidney source. Our findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying the development of end-stage renal disease in both types of diabetes. These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease, as well as biomarkers to measure responses to treatment of diabetic kidney disease. We conducted a 12-month clinical trial in 98 rural adult Zuni Indians with chronic kidney disease to examine the efficacy of a home-based kidney care program. Participants were randomized by household to receive usual care or home-based care. After initial lifestyle coaching, the intervention group received frequent additional reinforcement by community health representatives about adherence to medicines, diet and exercise, self-monitoring, and coping strategies for living with stress. The primary outcome was change in patient activation score, which assesses a participants knowledge, skill, and confidence in managing his/her own health and health care. Of 125 randomized individuals (63 intervention and 62 usual care), 98 (78%; 50 intervention and 48 usual care) completed the 12-month study. We concluded that home-based intervention improves participants activation in their own health and health care, and it may reduce risk factors for CKD in a rural disadvantaged population. In collaboration with the Renal Iohexol Clearance Study in Troms 6 (RENIS-T6), we examined the relationship between hyperfiltration and subsequent change decline in the GFR. We found that higher baseline GFR is associated with a faster decline in GFR over time, suggesting a role for hyperfiltration in the development of progressive kidney disease. Finally, we continue to publish from our consortial work. We published several papers with the CKD Biomarkers Consortium describing the role of adiposity in progressive kidney disease, the change in albuminuria and the subsequent risk of end-stage renal disease, and the relationship between measures of chronic kidney disease and other laboratory abnormalities.